Residue Based Contributions to Protein Stability and Association

 描述(申请人提供)：蛋白质变性的研究提供了关于稳定蛋白质结构和其他组装的力的关键信息。这对我们对蛋白质结构/功能方面的一般理解有重大影响，这些方面将直接影响我们对许多与蛋白质展开有关的疾病的理解， 错误折叠和聚合。虽然绝大多数研究都集中在蛋白质的天然状态上，但变性状态的作用也同样重要。目前人们普遍认为，变性态系综(DSE)在本质上不是随机的，而是可以具有残留的自然和非自然结构。虽然我们对自然态性质的认识已经被各种实验和模拟结果所推动，但我们对变性态的理解仍然有些简单化，主要是因为很难从实验中获得原子能级数据，并且我们无法从模拟中确定DSE的热力学性质。有人认为，结合使用涨落溶液理论的最新理论发展和计算机模拟方法，可以提供可靠的数据，说明由于残留物水平上压力、温度和组成的变化而产生的变性状态之间的异同。拟议中的项目有三个主要目标。目的1：确定残基对蛋白质热力学的贡献。目的：测定胰淀素及其突变体的热力学性质。目的3：确定环境对胰淀素小肽序列热力学和聚集性质的影响。这些研究的结果将提供有关变性状态的性质以及DSE在各种疾病中可能发挥作用的后果的有价值的信息。

 DESCRIPTION (provided by applicant): Studies of protein denaturation provide critical information concerning the forces that stabilize protein structure and other assemblies. This has a significant effect on our general understanding of the structure/function aspects of proteins that will directly impact our understanding of many diseases that are related to protein unfolding, misfolding, and aggregation. While the vast majority of studies have focused on the native state of proteins, the role of the denatured state is of equal importance. It is now generally accepted that the denatured state ensemble (DSE) is not random in nature but can possess residual native and non-native structure. While our knowledge of the properties of the native state has been advanced by a variety of experimental and simulation results, our understanding of the denatured state remains somewhat simplistic primarily due to the difficulties obtaining atomic level data from experiment, and our inability to determine the thermodynamic properties of the DSE from simulation. It is proposed that a combination of recent theoretical developments using Fluctuation Solution Theory, coupled with computer simulation approaches, can provide reliable data concerning the similarities and differences between denatured states generated by changes in pressure, temperature and composition at the residue level. There are three major aims to the proposed project. Aim 1: To Determine Residue Based Contributions to Protein Thermodynamics. Aim 2: To Determine the Thermodynamic Properties of Amylin and Mutant Amylin DSEs. Aim 3: To Determine the Effects of Environment on the Thermodynamic and Aggregation Properties of Small Peptide Sequences Derived from Amylin. The results of these studies will provide valuable information concerning the nature of the denatured state and the consequences for the role the DSE may play in a variety of diseases.